NSAID-Phosphatidylcholine Association: Insight in GI Ulcer Pathogenesis/Therapy

NSAID-磷脂酰胆碱协会：胃肠道溃疡发病机制/治疗的见解

• 批准号: 7817520
• 负责人: LENARD M LICHTENBERGER
• 金额: $ 49.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817520
• 关键词: Accounting; Address; Adverse effects; Affect; Alzheimer' s Disease; American; Anti Inflammatory Analgesics; Applications Grants; Area; Award; Bile Acids; Bile fluid; Biological; Biological Preservation; Cell Culture System; Cell Line; Cell Membrane Permeability; Cellular Membrane; Cessation of life; Characteristics; Chronic; Collaborations; Consumption; Coxibs; Development; Disease; Drug Formulations; Drug usage; Drug user; Dyes; Endoscopy; Energy Transfer; Equilibrium; Exclusion; Family; Fever; Fluorescent Probes; Gastrointestinal tract structure; Grant; Health; Hemorrhage; Ibuprofen; Inflammation; Injury; Institution; Intestines; Lecithin; Liposomes; Malignant Neoplasms; Membrane; Membrane Fluidity; Membrane Microdomains; Micelles; Modality; Mucous Membrane; NMR Spectroscopy; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Steroidal Anti-Inflammatory Agents; Nuclear Magnetic Resonance; Occupations; Pathogenesis; Pathway interactions; Permeability; Pharmaceutical Preparations; Phospholipids; Play; Property; Prostaglandin-Endoperoxide Synthase; Regulatory Pathway; Rodent Model; Rofecoxib; Role; Series; Small Intestines; Soybeans; Stomach; Stroke; Surface; Surface Plasmon Resonance; System; Techniques; Therapeutic; Thrombosis; Tissues; Translating; Translational Research; Treatment Efficacy; Ulcer; Universities; Withdrawal; base; capsule; cellular imaging; chemical association; clinically significant; cost; cytotoxic; extracellular; insight; light scattering; meetings; molecular dynamics; nanoparticle; novel; novel strategies; novel therapeutics; pain inhibition; pre-clinical; prevent; public health relevance; research study; soy; trend

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DK-103: "Translate discovery of new molecules/pathways in pathogenesis of NIDDK diseases in potential therapies." We have assembled a team of experts to characterize the mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) chemically associate with and destabilize phosphatidylcholine(PC) that plays an important role in the surface barrier property of the GI mucosa . This mechanism is independent of the ability of the drugs' to inhibit cyclooxygenase (COX) and is exacerbated by bile acids, that are present in high concentration to the lumen of the small intestine, by forming toxic mixed micelles due to their common amphipathic properties. The latter is consistent with recent capsule endoscopy evidence suggesting that NSAID-induced injury to the lower gut is much more prevalent than was once thought, affecting as much as 40% of chronic NSAID users. To elucidate the chemical associations between NSAIDs, PC and bile acids we propose to use: molecular dynamic (MD) simulation; surface plasmon resonance (SPR); and nuclear magnetic resonance (NMR) spectroscopy. To study the nanoparticles formed by these associations we propose a series of experiments with synthetic liposomal/micellar systems using: dynamic light scattering for size determination, and fluorescent probes such as, fluorescent resonance energy transfer (FRET) and dye exclusion analysis to assess the effects of NSAID bile acid interactions on membrane fluidity, microdomain formation and permeability. Studies on gastric and intestinal cell lines are proposed to evaluate the effects of our treatment on biological membranes as assessed by cellular - imaging (using fluorescent probes) - permeability and replication. These studies will then be translated to rodent models of NSAID-induced GI ulceration bleeding/ulceration and therapeutics, that are readily available in the PI's lab. Lastly, Challenge grant support will be used to partially defray the expense of performing the required formulation optimization, manufacturing and stability analyses of our first PC-NSAID under development (Ibuprofen-PC) by a university-based start-up company, PLx Pharma founded by the PI, to meet FDA requirements to obtain an New Drug Application, so that this novel class of GI-safer NSAIDs can be made available to the public. PUBLIC HEALTH RELEVANCE: Due to their remarkable efficacy to inhibit pain, inflammation and fever and their preventative efficacy for diseases such as cancer, stroke, thrombosis and Alzheimer's disease, it has been estimated that NSAIDs are consumed by ~70 million Americans on a chronic basis. The major health concern with this trend, is that the consumption of NSAIDs is well known to be associated with side-effects, with GI ulceration and bleeding being most common, accounting for 400,000 people being hospitalized at an estimated cost of $ 124.8 billion/yr and 16,000-20,000 deaths annually. With the withdrawal of selective COX-2 inhibitors, such as Vioxx, there is a great "unmet need" for novel strategies to understand and prevent NSAID-induced GI side-effects. This Translational Science Challenge grant is focused on understanding how NSAIDs chemically associate with and destabilize phosphatidylcholine(PC) that plays an important role in the surface barrier property of the GI mucosa. Furthermore, by pre-associating soy PC with NSAIDs we have developed a novel family GI-safer, therapeutically effective PC-NSAIDs that can be made available to the public using an accelerated FDA regulatory pathway.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15) 转化科学和具体挑战主题 15-DK-103：“将 NIDDK 疾病发病机制中新分子/途径的发现转化为潜在疗法。”我们组建了一个专家团队来研究非甾体抗炎药 (NSAID) 与磷脂酰胆碱 (PC) 发生化学结合并使其不稳定的机制，而磷脂酰胆碱 (PC) 在胃肠道粘膜的表面屏障特性中发挥着重要作用。这种机制与药物抑制环氧合酶 (COX) 的能力无关，并且由于胆汁酸以高浓度存在于小肠腔中，由于其共同的两亲特性而形成有毒的混合胶束，从而加剧了这种机制。后者与最近的胶囊内窥镜检查证据一致，表明 NSAID 引起的下肠道损伤比以前想象的要普遍得多，影响了多达 40% 的长期 NSAID 使用者。为了阐明 NSAID、PC 和胆汁酸之间的化学关联，我们建议使用：分子动力学 (MD) 模拟；表面等离子共振（SPR）；和核磁共振（NMR）光谱。为了研究由这些缔合形成的纳米粒子，我们提出了一系列合成脂质体/胶束系统的实验，使用：用于尺寸测定的动态光散射，以及用于评估效果的荧光探针，例如荧光共振能量转移（FRET）和染料排除分析NSAID 胆汁酸相互作用对膜流动性、微区形成和渗透性的影响。建议对胃和肠细胞系进行研究，以评估我们的治疗对生物膜的影响，通过细胞成像（使用荧光探针）渗透性和复制来评估。然后，这些研究将转化为非甾体抗炎药引起的胃肠道溃疡出血/溃疡和治疗的啮齿动物模型，这些模型在 PI 实验室中很容易获得。最后，挑战赛拨款支持将用于部分支付我们正在开发的第一个 PC-NSAID（布洛芬-PC）所需的配方优化、制造和稳定性分析的费用，该药物由一家大学初创公司 PLx Pharma 创立由 PI 负责，以满足 FDA 获得新药申请的要求，以便向公众提供这种新型的胃肠道更安全的非甾体抗炎药。 公共健康相关性：由于非甾体抗炎药具有显着的抑制疼痛、炎症和发烧功效，以及对癌症、中风、血栓形成和阿尔茨海默病等疾病的预防功效，据估计约有 7000 万美国人长期服用非甾体抗炎药。这一趋势带来的主要健康问题是，众所周知，服用非甾体抗炎药会产生副作用，其中最常见的是胃肠道溃疡和出血，导致 40 万人住院，每年的费用估计为 1,248 亿美元每年有 16,000-20,000 人死亡。随着 Vioxx 等选择性 COX-2 抑制剂的退出，对于理解和预防 NSAID 引起的胃肠道副作用的新策略存在巨大的“未满足的需求”。这项转化科学挑战赛资助的重点是了解非甾体抗炎药如何与磷脂酰胆碱 (PC) 发生化学关联并使其不稳定，而磷脂酰胆碱 (PC) 在胃肠道粘膜的表面屏障特性中发挥着重要作用。此外，通过将大豆 PC 与 NSAID 预先关联，我们开发了一种新型的胃肠道更安全、治疗有效的 PC-NSAID，可以通过 FDA 加速监管途径向公众提供。